Scientists unveiled a genomics platform called PerturbFate that identified a shared vulnerability across hundreds of cancer-linked mutations by tracking how different genetic disruptions push cells toward the same drug-resistant state.
Researchers at Rockefeller University profiled more than 300,000 melanoma cells after systematically shutting down 140 genes associated with resistance to the BRAF inhibitor vemurafenib. Despite diverse mutations, many perturbations converged on a dedifferentiated cell state driven by MAPK and Hippo signaling pathways.
The Nature study found transcription factors including FOSL1 and TEAD family members act as cooperative hubs for resistance. When scientists targeted these convergent control points, drug resistance declined significantly in laboratory models, suggesting combination therapies could address multiple genetic causes simultaneously.
Authors said PerturbFate integrates chromatin accessibility, nascent RNA and steady-state transcriptomics in single cells over time. The team made tools publicly available and plans to apply the platform to Alzheimer’s disease and aging research where many mutations also produce overlapping cellular outcomes.
PerturbFate combined CRISPR perturbations with single-cell profiling of chromatin accessibility and nascent transcription in A375 melanoma cells treated with vemurafenib. The Nature study linked Mediator complex disruptions to convergent gene activation programs driving dedifferentiation. Rockefeller researchers said the platform could next explore Alzheimer’s and aging where diverse mutations produce overlapping disease states.
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Sources:
https://www.sciencedaily.com/